PARP Inhibitors in breast cancer

Poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors and breast cancer

• PARP‐1 and PARP‐2 proteins are part of the complex that is assembled in response to single‐strand deoxyribonucleic acid (DNA) breaks and are integral to the repair of single‐strand DNA breaks
• PARP inhibitors promote the progression of single‐strand DNA breaks to double‐strand DNA breaks and can induce synthetic lethality in cells with impaired homologous recombination mechanisms, such as those with a BRCA mutation
  • BRCA1 and BRCA2 genes play a part in cell repair in the body
    • cells are less likely to repair themselves if there is a fault in one or both of these genes
    • cancer cells with BRCA gene faults already have a poor repair system
      • therefore blocking PARP with a PARP inhibitor drug means that the cells are not able to repair themselves and apoptosis occurs
• a systematic review concluded (1):
  • people with locally advanced or metastatic HER2‐negative, BRCA germline mutated breast cancer, PARP inhibitors offer an improvement in progression‐free survival, and likely improve overall survival and tumour response rates
• a review notes that studies have shown that the benefit of PARP inhibitors extends beyond patients with germline BRCA1/2-associated metastatic breast cancer to patients with somatic BRCA1/2 variants and to those with germline PALB2 alterations (2)
  • notes that these agents proved to be effective both in the metastatic and adjuvant settings

Reference:

• Taylor AM, Chan DLH, Tio M, Patil SM, Traina TA, Robson ME, Khasraw M. PARP (Poly ADP-Ribose Polymerase) inhibitors for locally advanced or metastatic breast cancer. Cochrane Database Syst Rev. 2021 Apr 22;4(4):CD011395.
• Morganti S, Marra A, De Angelis C, et al. PARP Inhibitors for Breast Cancer Treatment: A Review. JAMA Oncol. Published online March 21, 2024. doi:10.1001/jamaoncol.2023.7322